See 17 for PATIENT COUNSELING INFORMATION and FDAapproved

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use STRIBILD safely and effectively. See full prescribing information for STRIBILD. STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets, for oral use Initial U.S. Approval: 2012 WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (DF), a component of STRIBILD. (5.1) STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, two of the components of STRIBILD. Hepatic function should be monitored closely in these patients. If appropriate, initiation of antihepatitis B therapy may be warranted. (5.2) RECENT MAJOR CHANGES Contraindications (4) 09/2016 Warnings and Precautions Avoid Use with Other Antiretroviral Products (5.4) 09/ INDICATIONS AND USAGE STRIBILD is a four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir DF, both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/ml) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD. (1, 14) DOSAGE AND ADMINISTRATION Recommended dosage: One tablet taken once daily with food. (2.1) Dosage in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 ml per minute is not recommended. Discontinue in patients with estimated creatinine clearance below 50 ml per minute. (2.2) DOSAGE FORMS AND STRENGTHS Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate. (3) CONTRAINDICATIONS Coadministration of STRIBILD is contraindicated with drugs that: Are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious adverse events. (4) Strongly induce CYP3A, which may lead to lower exposure of one or more components and loss of efficacy of STRIBILD and possible resistance. (4) WARNINGS AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CLcr), urine glucose, and urine protein before initiating treatment with STRIBILD. Monitor CLcr, urine glucose, and urine protein in all patients. Monitor serum phosphorus in patients at risk for renal impairment. Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs. (5.3) Avoid coadministration with other antiretroviral products: Do not use with products containing any of the components of STRIBILD (cobicistat, elvitegravir, emtricitabine, and tenofovir disoproxil fumarate) or tenofovir alafenamide, including ATRIPLA, COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, TRUVADA, TYBOST, VIREAD, or VITEKTA; with drugs containing lamivudine; or with drugs or regimens containing ritonavir. Do not administer in combination with HEPSERA. (5.4) Risk of adverse reactions or loss of virologic response due to drug interactions: The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of STRIBILD and possible development of resistance; and possible clinically significant adverse reactions from greater exposures of concomitant drugs. (5.5) Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.6) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.7) Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.8) ADVERSE REACTIONS Most common adverse drug reactions to STRIBILD (incidence greater than or equal to 10%, all grades) are nausea and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at GILEAD-5 or FDA at FDA-1088 or DRUG INTERACTIONS STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. (5.4, 7.1) STRIBILD can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of one or more components of STRIBILD. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions. (4, 7.2, 7.3, 12.3) USE IN SPECIFIC POPULATIONS Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk. (8.1) Nursing mothers: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: 09/2016 1

2 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosage Information 2.2 Dosage Adjustment in Patients with Renal Impairment 2.3 Dosage in Patients with Hepatic Impairment 2.4 Testing Prior to Initiation of STRIBILD 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis 5.2 Patients Coinfected with HIV-1 and HBV 5.3 New Onset or Worsening Renal Impairment 5.4 Avoid Use with Other Antiretroviral Products 5.5 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions 5.6 Bone Effects of Tenofovir DF 5.7 Fat Redistribution 5.8 Immune Reconstitution Syndrome 6 ADVERSE REACTIONS 6.1 Adverse Reactions from Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Other Antiretroviral Medications 7.2 Potential for STRIBILD to Affect Other Drugs 7.3 Potential for Other Drugs to Affect One or More Components of STRIBILD 7.4 Drugs Affecting Renal Function 7.5 Established and Other Potentially Significant Interactions 7.6 Drugs without Clinically Significant Interactions with STRIBILD 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. 2

3 FULL PRESCRIBING INFORMATION WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of STRIBILD, in combination with other antiretrovirals [See Warnings and Precautions (5.1)]. STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and human immunodeficiency virus-1 (HIV-1). Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or VIREAD, which are components of STRIBILD. Hepatic function should be monitored closely, with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue STRIBILD. If appropriate, initiation of antihepatitis B therapy may be warranted [See Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE STRIBILD is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/ml) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of STRIBILD [See Clinical Studies (14)]. 2 DOSAGE AND ADMINISTRATION 2.1 Dosage Information The recommended dosage of STRIBILD is one tablet taken orally once daily with food [See Clinical Pharmacology (12.3)]. 2.2 Dosage Adjustment in Patients with Renal Impairment Initiation of STRIBILD in patients with estimated creatinine clearance below 70 ml per minute is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 ml per minute during treatment with STRIBILD, as the dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved [See Warnings and Precautions (5.3), Adverse Reactions (6.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Clinical Studies (14)]. 3

4 2.3 Dosage in Patients with Hepatic Impairment No dosage adjustment of STRIBILD is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of STRIBILD in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, STRIBILD is not recommended for use in patients with severe hepatic impairment [See Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. 2.4 Testing Prior to Initiation of STRIBILD Prior to initiation of STRIBILD, patients should be tested for hepatitis B infection [See Warnings and Precautions (5.2)] and estimated creatinine clearance, urine glucose, and urine protein should be documented in all patients [See Warnings and Precautions (5.3)]. 3 DOSAGE FORMS AND STRENGTHS Each STRIBILD tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil). The tablets are green, capsule shaped, film coated, and debossed with GSI on one side and the number 1 surrounded by a square box ( 1 ) on the other side. 4 CONTRAINDICATIONS Coadministration of STRIBILD is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of STRIBILD and possible resistance) are listed in Table 1 [See Drug Interactions (7.5) and Clinical Pharmacology (12.3)]. Table 1 Drugs that are Contraindicated with STRIBILD Drug Class Alpha 1-Adrenoreceptor Antagonist Anticonvulsants Drugs within Class that are Contraindicated with STRIBILD Alfuzosin Carbamazepine Phenobarbital Phenytoin Clinical Comment Potential for increased alfuzosin concentrations, which can result in hypotension. Potential for decreased cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Antimycobacterial Rifampin Rifampin is a potent inducer of CYP450 metabolism and may cause significant decrease in the plasma concentration of elvitegravir and cobicistat. This may result in loss of therapeutic effect to STRIBILD. 4

5 Antipsychotic Ergot Derivatives Lurasidone Pimozide Dihydroergotamine Ergotamine Methylergonovine Potential for serious and/or life-threatening reactions. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI Motility Agent Cisapride Potential for serious and/or life-threatening events such as cardiac arrhythmias. Herbal Products HMG-CoA Reductase Inhibitors St. John s wort (Hypericum perforatum) Lovastatin Simvastatin Coadministration of products containing St. John s wort and STRIBILD may result in reduced plasma concentrations of elvitegravir and cobicistat. This may result in loss of therapeutic effect and development of resistance. Potential for serious reactions such as myopathy, including rhabdomyolysis. Phosphodiesterase-5 (PDE-5) Inhibitor Sildenafil a when dosed as Revatio for the treatment of pulmonary arterial hypertension There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope). Sedative/Hypnotics Triazolam Orally administered midazolam b Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with STRIBILD may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression. a. See Drug Interactions (7), Table 6, for sildenafil when dosed as Viagra for erectile dysfunction. b. See Drug Interactions (7), Table 6, for parenterally administered midazolam. 5 WARNINGS AND PRECAUTIONS 5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, a component of STRIBILD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with STRIBILD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5

6 5.2 Patients Coinfected with HIV-1 and HBV It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. STRIBILD is not approved for the treatment of chronic HBV infection, and the safety and efficacy of STRIBILD have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of STRIBILD. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with STRIBILD. If appropriate, initiation of antihepatitis B therapy may be warranted. 5.3 New Onset or Worsening Renal Impairment Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF, a component of STRIBILD, and with the use of STRIBILD [See Adverse Reactions (6.2)]. In the clinical trials of STRIBILD over 144 weeks, 13 (1.9%) subjects in the STRIBILD group (N=701), 8 (2.3%) subjects in the atazanavir (ATV) + ritonavir (RTV) + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) group (N=355), and no subjects in the ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg) group (N=352) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 8 in the STRIBILD group and 1 in the ATV+RTV+TRUVADA group occurred during the first 48 weeks. Four (0.6%) subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction, leading to discontinuation of STRIBILD during the first 48 weeks of treatment. Two of the four subjects had renal impairment (i.e., estimated creatinine clearance less than 70 ml per minute) at baseline. The laboratory findings in these 4 subjects improved but did not completely resolve in all subjects upon discontinuation of STRIBILD. Renal replacement therapy was not required for these subjects. One (0.3%) subject who received ATV+RTV+TRUVADA developed laboratory findings consistent with proximal renal tubular dysfunction, leading to discontinuation of ATV+RTV+TRUVADA after Week 96. STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [See Drug Interactions (7.4)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. 6

7 Estimated creatinine clearance, urine glucose, and urine protein should be documented in all patients prior to initiating therapy. Initiation of STRIBILD in patients with estimated creatinine clearance below 70 ml per minute is not recommended. Routine monitoring of estimated creatinine clearance, urine glucose, and urine protein should be performed during STRIBILD therapy in all patients. Additionally, serum phosphorus should be measured in patients at risk for renal impairment. Although cobicistat (a component of STRIBILD) may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function [See Adverse Reactions (6.1)], patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dl from baseline should be closely monitored for renal safety. The emtricitabine and tenofovir DF components of STRIBILD are primarily excreted by the kidney. STRIBILD should be discontinued if estimated creatinine clearance declines below 50 ml per minute as dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved with the fixed-dose combination tablet. 5.4 Avoid Use with Other Antiretroviral Products STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection, and coadministration with other antiretroviral products is not recommended. STRIBILD is not recommended for coadministration with the following: cobicistat (TYBOST ) elvitegravir (VITEKTA ) products containing emtricitabine, tenofovir DF, or tenofovir alafenamide (ATRIPLA, COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, TRUVADA, VIREAD ) products containing lamivudine (Combivir, Epivir, Epivir-HBV, Epzicom, Triumeq, Trizivir) adefovir dipivoxil (HEPSERA ) products containing ritonavir (Norvir, Kaletra). 5.5 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of STRIBILD and other drugs may result in known or potentially significant drug interactions, some of which may lead to [See Contraindications (4) and Drug Interactions (7.5)]: Loss of therapeutic effect of STRIBILD and possible development of resistance. Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [See Drug Interactions (7.5)]. Consider 7

8 the potential for drug interactions prior to and during STRIBILD therapy; review concomitant medications during STRIBILD therapy; and monitor for the adverse reactions associated with the concomitant drugs. 5.6 Bone Effects of Tenofovir DF Bone Mineral Density In clinical trials in HIV-1-infected adults, tenofovir DF (a component of STRIBILD) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1.25 Vitamin D levels were also higher in subjects receiving tenofovir DF. For additional information, see Adverse Reactions (6.1) and consult the VIREAD prescribing information. The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1-infected patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial in all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained. Mineralization Defects Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF [See Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF [See Warnings and Precautions (5.3)]. 5.7 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as 8

9 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning and Warnings and Precautions (5.1)]. Severe Acute Exacerbations of Hepatitis B [See Boxed Warning and Warnings and Precautions (5.2)]. New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)]. Bone Effects of Tenofovir DF [See Warnings and Precautions (5.6)]. Immune Reconstitution Syndrome [See Warnings and Precautions (5.8)]. 6.1 Adverse Reactions from Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In HIV-1-Infected Subjects with No Antiretroviral Treatment History The safety assessment of STRIBILD is based on the Week-144 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naïve HIV-1-infected adult subjects [See Clinical Studies (14)]. A total of 701 subjects received STRIBILD once daily in these two studies. The proportion of subjects who discontinued treatment with STRIBILD, ATRIPLA, or ATV+RTV+TRUVADA due to adverse events, regardless of severity, was 6.0%, 7.4%, and 8.5%, respectively. Table 2 displays the frequency of adverse reactions greater than or equal to 5% of subjects in any treatment arm. 9

10 Table 2 Adverse Reactions a (All Grades) Reported in 5% of Subjects in Any Treatment Arm in Studies 102 and 103 (Week-144 Analysis) EYE DISORDERS STRIBILD N=701 ATRIPLA N=352 ATV+RTV+ TRUVADA N=355 Ocularicterus <1% 0% 13% GASTROINTESTINAL DISORDERS Diarrhea 12% 11% 17% Flatulence 2% <1% 8% Nausea 16% 9% 14% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 4% 8% 6% HEPATOBILIARY DISORDERS Jaundice 0% <1% 9% NERVOUS SYSTEM DISORDERS Somnolence 1% 7% 1% Headache 7% 4% 6% Dizziness 3% 21% 5% PSYCHIATRIC DISORDERS Insomnia 3% 9% 1% Abnormal dreams 9% 27% 4% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash b 4% 15% 6% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drugs. b. Rash event includes dermatitis, drug eruption, eczema, pruritus, pruritus generalized, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, and urticaria. See Warnings and Precautions (5.3) for a discussion of renal adverse reactions from clinical trials experience with STRIBILD. Additional adverse reactions observed with STRIBILD included suicidal ideation and suicide attempt (0.3%), all in subjects with a preexisting history of depression or psychiatric illness. In Virologically Suppressed HIV-1-Infected Subjects No new adverse reactions to STRIBILD through Week 48 were identified in 584 virologically stably suppressed subjects switching to STRIBILD from a regimen containing a RTV-boosted protease inhibitor (PI) or a non-nucleoside reverse 10

11 transcriptase inhibitor (NNRTI). In a combined analysis of studies 115 and 121, the frequency of adverse reactions (all grades) was 24% in subjects switching to STRIBILD compared to 6% of subjects in either group who stayed on their baseline antiretroviral regimen, RTV-boosted PI+TRUVADA or NNRTI+TRUVADA. Common adverse reactions that occurred in greater than or equal to 2% of subjects switching to STRIBILD were nausea (4%), flatulence (2%), and headache (2%). The proportion of subjects who discontinued treatment with STRIBILD, the RTV-boosted PI, or the NNRTI due to adverse events was 2%, 3%, and 1%, respectively. Adverse Reactions from Clinical Trials of the Components of STRIBILD Emtricitabine and Tenofovir Disoproxil Fumarate: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3 4) occurring in at least 2% of subjects receiving STRIBILD in studies 102 and 103 are presented in Table 3. Table 3 Laboratory Abnormalities (Grades 3 4) Reported in 2% of Subjects Receiving STRIBILD in Studies 102 and 103 (Week-144 Analysis) Laboratory Parameter Abnormality a,b STRIBILD N=701 ATRIPLA N=352 ATV+RTV+ TRUVADA N=355 AST (>5.0 x ULN) 3% 6% 6% ALT (>3.0 x ULN) 2% 5% 4% Amylase a (>2.0 x ULN) 3% 3% 5% Creatine Kinase (10.0 x ULN) 8% 15% 11% Urine RBC (Hematuria) (>75 RBC/HPF) 4% 2% 4% a. Frequencies are based on treatment-emergent laboratory abnormalities. b. For subjects with serum amylase >1.5 x upper limit of normal (ULN), lipase test was also performed. The frequency of increased lipase (Grades 3 4) occurring in STRIBILD (N=69), ATRIPLA (N=40), and ATV+RTV+TRUVADA (N=38) was 17%, 15%, and 24%, respectively. In Study 103, BMD was assessed by DEXA in a nonrandom subset of 120 subjects (STRIBILD group, N=54; ATV+RTV+TRUVADA group, N=66). Mean percentage decreases in BMD from baseline to Week 144 in the STRIBILD group were comparable 11

12 to that in the ATV+RTV+TRUVADA group at the lumbar spine ( 1.43% versus 3.68%, respectively) and at the hip ( 2.83% versus 3.77%, respectively). In studies 102 and 103, bone fractures occurred in 27 subjects (3.9%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 19 subjects (5.4%) in the ATV+RTV+TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naïve subjects receiving tenofovir DF + lamivudine + efavirenz. Proteinuria (all grades) occurred in 52% of subjects receiving STRIBILD, 41% of subjects receiving ATRIPLA, and 42% of subjects receiving ATV+RTV+TRUVADA. The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which levels stabilized. Table 4 displays the mean changes in serum creatinine and egfr levels at Week 144 and the percentage of subjects with elevations in serum creatinine (all grades). Table 4 Change from Baseline in Serum Creatinine and egfr and Incidence of Elevated Serum Creatinine (All Grades) in Studies 102 and 103 at Week 144 STRIBILD N=701 ATRIPLA N=352 ATV+RTV+ TRUVADA N=355 Serum Creatinine (mg/dl) a 0.14 (±0.14) 0.01 (±0.12) 0.09 (±0.15) egfr by Cockcroft-Gault a 14.0 (±16.6) 1.9 (±17.9) 9.8 (±19.4) (ml/minute) Subjects with Elevations in Serum Creatinine (All Grades) (%) a. Mean change ± standard deviation Emtricitabine or Tenofovir Disoproxil Fumarate: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of ALT (M: greater than 215 U per L; F: greater than 170 U per L), alkaline phosphatase (greater than 550 U per L), bilirubin (greater than 2.5 x ULN), serum glucose (less than 40 or greater than 250 mg per dl), glycosuria (greater than or equal to 3+), neutrophils (less than 750 per mm 3 ), fasting cholesterol (greater than 240 mg per dl), and fasting triglycerides (greater than 750 mg per dl). Serum Lipids: In the clinical trials of STRIBILD, a similar percentage of subjects receiving STRIBILD, ATRIPLA, and ATV+RTV+TRUVADA were on lipid-lowering agents at baseline (12%, 12%, and 13%, respectively). While receiving study drug through Week 144, an additional 11% of STRIBILD subjects were started on lipidlowering agents, compared to 13% of ATRIPLA and 12% of ATV+RTV+TRUVADA subjects. 12

13 Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5. Table 5 Lipid Values, Mean Change from Baseline at Week 144 in Subjects Receiving STRIBILD or Comparator in Studies 102 and 103 Total Cholesterol (fasted) HDLcholesterol (fasted) LDLcholesterol (fasted) Triglycerides (fasted) STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 Baseline Week 144 Baseline Week 144 Baseline Week 144 mg/dl Change a mg/dl Change a mg/dl Change a 166 [N=675] 43 [N=675] 100 [N=675] 122 [N=675] +17 [N=535] +7 [N=535] +15 [N=535] +12 [N=535] 161 [N=343] 43 [N=343] 97 [N=343] 121 [N=343] +22 [N=262] +9 [N=262] +19 [N=262] +5 [N=262] 168 [N=337] 42 [N=335] 101 [N=337] 132 [N=337] +16 [N=243] +7 [N=242] +18 [N=242] +22 [N=242] a. The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of tenofovir DF. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. No additional postmarketing adverse reactions specific for emtricitabine have been identified. Immune System Disorders allergic reaction, including angioedema Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders dyspnea Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders rash 13

14 Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia. 7 DRUG INTERACTIONS See also Contraindications (4) and Clinical Pharmacology (12.3). 7.1 Other Antiretroviral Medications STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided. 7.2 Potential for STRIBILD to Affect Other Drugs Cobicistat, a component of STRIBILD, is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: P-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. Thus, coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3, may result in increased plasma concentrations of such drugs. Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates. 7.3 Potential for Other Drugs to Affect One or More Components of STRIBILD Elvitegravir and cobicistat, components of STRIBILD, are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6. Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance (See Table 6). Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (See Table 6). 14

15 7.4 Drugs Affecting Renal Function Because emtricitabine and tenofovir, components of STRIBILD, are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [See Warnings and Precautions (5.3)]. 7.5 Established and Other Potentially Significant Interactions Table 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either STRIBILD or the components of STRIBILD (elvitegravir, cobicistat, emtricitabine, and tenofovir DF) as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD [for magnitude of interaction, See Clinical Pharmacology (12.3)]. The table includes potentially significant interactions but is not all inclusive. Table 6 Established and Other Potentially Significant a Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Acid Reducing Agents: Antacids* e.g., aluminum and magnesium hydroxide Antiarrhythmics: e.g., amiodarone bepridil digoxin* disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine Antibacterials: clarithromycin Effect on Concentration b elvitegravir antiarrhythmics digoxin clarithromycin cobicistat Clinical Comment Separate STRIBILD and antacid administration by at least 2 hours. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD. Patients with CLcr greater than or equal to 60 ml/minute: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 ml/minute and 60 ml/minute: 15

16 The dose of clarithromycin should be reduced by 50%. Anticoagulants: warfarin Anticonvulsants: oxcarbazepine Effect on warfarin unknown elvitegravir cobicistat Monitor international normalized ratio (INR) upon coadministration of warfarin with STRIBILD. Contraindicated anticonvulsants [see Contraindications (4)] clonazepam ethosuximide Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline bupropion trazodone Antifungals: itraconazole ketoconazole* voriconazole Anti-gout: colchicine clonazepam ethosuximide SSRIs TCAs trazodone elvitegravir cobicistat itraconazole ketoconazole voriconazole colchicine Alternative anticonvulsants should be considered when STRIBILD is coadministered with oxcarbazepine. Clinical monitoring is recommended upon coadministration of clonazepam or ethosuximide with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended when coadministered with STRIBILD. When coadministered with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD. STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout-flares coadministration of colchicine in patients receiving STRIBILD: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares coadministration of colchicine in patients receiving STRIBILD: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. 16

17 Antimycobacterial: rifabutin* rifapentine Antipsychotics: e.g., perphenazine risperidone thioridazine quetiapine elvitegravir cobicistat antipsychotic quetiapine Treatment of familial Mediterranean fever coadministration of colchicine in patients receiving STRIBILD: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Contraindicated antimycobacterials [see Contraindications (4)] Coadministration of STRIBILD with rifabutin or rifapentine is not recommended. Contraindicated antipsychotics [see Contraindications (4)] A decrease in the dose of antipsychotics that are metabolized by CYP3A4 or CYP2D6 may be needed when coadministered with STRIBILD. Initiation of STRIBILD in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Beta-Blockers: e.g., metoprolol timolol Calcium Channel Blockers: e.g., amlodipine diltiazem felodipine nicardipine nifedipine verapamil Corticosteroid: Systemic: dexamethasone Corticosteroid: Inhaled/Nasal: fluticasone beta-blockers calcium channel blockers elvitegravir cobicistat fluticasone Initiation of quetiapine in patients taking STRIBILD: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Clinical monitoring is recommended and a dose decrease of the beta-blocker may be necessary when these agents are coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration of calcium channel blockers with STRIBILD. Alternative corticosteroids should be considered. Concomitant use of STRIBILD with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long-term use. 17

18 Endothelin Receptor Antagonists: bosentan bosentan Coadministration of bosentan in patients on STRIBILD: In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir HMG-CoA Reductase Inhibitors: atorvastatin Hormonal Contraceptives: norgestimate/ethinyl estradiol* Immunosuppressants: e.g., cyclosporine sirolimus tacrolimus Narcotic Analgesics: buprenorphine/ naloxone* Inhaled Beta Agonist: salmeterol tenofovir atorvastatin norgestimate ethinyl estradiol immunosuppressants buprenorphine norbuprenorphine naloxone salmeterol Coadministration of STRIBILD in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. The safety of increased tenofovir concentrations in the setting of HARVONI and STRIBILD has not been established. Coadministration is not recommended. Contraindicated HMG-CoA Reductase Inhibitors [see Contraindications (4)] Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety. The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (nonhormonal) methods of contraception can be considered. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects. Coadministration of salmeterol and STRIBILD is not recommended because it may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. 18

19 Phosphodiesterase-5 (PDE-5) Inhibitors: sildenafil tadalafil vardenafil PDE-5 inhibitors Contraindicated PDE-5 Inhibitors [see Contraindications (4)] Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of tadalafil for pulmonary arterial hypertension (PAH): Coadministration of tadalafil in patients on STRIBILD: In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability. Coadministration of STRIBILD in patients on tadalafil: Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability. Sedative/hypnotics: Benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem Use of PDE-5 inhibitors for erectile dysfunction: The below PDE-5 inhibitors can be used along with increased monitoring for PDE-5-inhibitor associated adverse events: Sildenafil at a single dose not exceeding 25 mg in 48 hours, or Tadalafil at a single dose not exceeding 10 mg in 72 hours, or Vardenafil at a single dose not exceeding 2.5 mg in 72 hours sedatives/hypnotics Contraindicated sedative/hypnotics [see Contraindications (4)] Coadministration of parenteral midazolam with STRIBILD should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended. * Indicates that a drug-drug interaction trial was conducted. a. This table is not all inclusive. b. =Increase, =Decrease, =No Effect 19

20 7.6 Drugs without Clinically Significant Interactions with STRIBILD Based on drug interaction studies conducted with the components of STRIBILD, no clinically significant drug interactions have been either observed or are expected when STRIBILD is combined with the following drugs: entecavir, famciclovir, H 2 receptor antagonists, methadone, proton pump inhibitors, and ribavirin. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to STRIBILD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, STRIBILD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Elvitegravir: Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with elvitegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg. Cobicistat: Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal NOAELs in rats and rabbits were respectively 1.8 and 4.3 times higher than the exposure in humans at the recommended daily dose of 150 mg. Emtricitabine: The incidence of fetal variations and malformations was not increased in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body-surface-area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. 20